Exposure of a fetus to ethanol can lead to development of fetal alcohol syndrome, which is characterized by various morphological and behavioral deficits in fetal alcohol-exposed offspring. These offspring often show abnormalities in stress responses. Recent studies have revealed a possibility that the stress response anomalies seen in the FAE offspring are related to the functional abnormalities of hypothalamic beta-endorphin- (b-EP) producing neurons. However, there is not sufficient information available on the effect of ethanol on b-endorphin neuronal growth and differentiation. The present proposal will address this issue by studying the in vivo and in vitro effects of ethanol on beta-endorphin neuron growth and differentiation using rat as an animal model. The proposed research will test the hypotheses that ethanol exposure during the developmental period induces programmed cell death in b-EP neurons and that cAMP and transforming growth factor-beta1 (TGF-beta1) may be involved in controlling the ethanol-induced neurotoxicity. Specific objectives of this proposal are to: 1) determine the action of ethanol on b-EP neuronal growth and differentiation and the consequence on the development of the functional b-EP neurons, 2) identify the role of the cAMP system in ethanol neurotoxic action on b-EP neurons, 3) evaluate the role of TGF-beta in ethanol neurotoxic action on b-EP neurons, 4) study the signaling mechanisms of the ethanol neurotoxic action on b-EP neurons. Ethanol's action on programmed cell death in the b-EP neurons will be studied both in vivo and in vitro using biochemical and immunocytochemical techniques. The mechanism of ethanol's neurotoxic action on b-EP neurons will be determined using a rat fetal hypothalamic neuronal cell culture system. Two-pronged approaches will be applied to study the mechanisms of the ethanol neurotoxic action; one to pharmacologically manipulate the signal transduction systems, another to measure the intracellular level of these signal transducers by histological, biochemical and molecular techniques.